Inhibitory effects of PPAR-γ on endothelin-1-induced inflammatory pathways in vascular smooth muscle cells from normotensive and hypertensive rats

Abstract 

The present study evaluated the effects of endothelin (ET)-1 and the peroxisome proliferator activated receptor γ (PPAR-γ) agonist, rosiglitazone, on inflammatory markers in vascular smooth muscle cells (VSMCs) from normotensive (WKY) and hypertensive (SHRSP) rats. Rat VSMC-derived mesenteric arteries from WKY and SHRSP were treated with ET-1 (100 mmol/L) and rosiglitazone (1μmol/L) or ET type A (ET_A) or type B (ET_B) receptor antagonists. Nuclear factor kappa-B (NFκB) binding activity was assessed by electrophoretic mobility shift assay and phospho-inhibitory κB (IκB); vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, and cyclooxygenase (COX)-2 expression was determined using Western blotting. ET-1 significantly increased NFκB binding, and VCAM-1, ICAM, and COX-2 expression to a greater degree in SHRSP than in WKY VSMC. These changes were associated with increased phosphorylation of IκB, thus resulting in decreased NFκB inhibition. Co-incubation with PPAR-γ activator rosiglitazone, or ET_A or ET_B receptor antagonism prevented ET-1-stimulated vascular proinflammatory effects in both WKY and SHRSP VSMC. Proinflammatory effects of ET-1 in VSMCs are mediated via both ET_A and ET_B receptor subtypes. These effects may be abrogated by the PPAR-γ activator rosiglitazone. PPAR-γ activators may thus prevent deleterious ET-1-dependent proinflammatory vascular effects in VSMC in hypertension.

Keywords: Adhesion molecules, NFκB, VCAM-1, COX-2, endothelin receptors, rosiglitazone